Acute Respiratory Distress Syndrome, Coronavirus Infections, Pneumonia, Viral
Conditions
Keywords
COVID-19, ARDS, Mechanical Ventilation, Nitric Oxide
Brief summary
The scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Some preliminary data on SARS pneumonia suggest that inhaled Nitric Oxide (NO) could have beneficial effects on SARS-CoV-2 due to the genomic similarities between this two coronaviruses. In this study we will test whether inhaled NO therapy prevents progression in patients with mild to moderate COVID-19 disease.
Detailed description
To date, no targeted therapeutic treatments for the ongoing COVID-19 outbreak have been identified. Antiviral combined with adjuvant therapies are currently under investigation. The clinical spectrum of the infection is wide, ranging from mild signs of upper respiratory tract infection to severe pneumonia and death. In the patients who progress, the time period from symptoms onset to development of dyspnea is reported to be between 5 to 10 days, and that one to severe respiratory distress syndrome from 10 to 14 days. Globally, 15 to 18% of patients deteriorates to the need of mechanical ventilation, despite the use of non-invasive ventilatory support in the earliest phases of the disease. Probability of progression to end stage disease is unpredictable, with the majority of these patients dying from multi-organ failure. Preventing progression in spontaneously breathing patients with mild to moderate disease would translate in improved morbidity and mortality and in a lower use of limited healthcare resources. In 2004, during the SARS-coronavirus (SARS-CoV) outbreak, a pilot study showed that low dose ( max 30 ppm) inhaled NO for 3 days was able to shorten the time of ventilatory support. At the same time, NO donor compound S-nitroso-N-acetylpenicillamine increased survival rate in an in-vitro model of SARS-CoV infected epithelial cells.Based on the genetic similarities between the two viruses, similar effects of NO on SARS-CoV-2 can be hypothesized. While further in-vitro testing is recommended, we proposed a randomized clinical trial to test the effectiveness of inhaled NO in preventing the progression of SARS-CoV-2 related disease, when administered at an early stage.
Interventions
DRUGNitric Oxide
Nitric Oxide (NO) will be delivered together with the standard of care for a period of 20-30 minutes 2 times per day for 14 consecutive days from time of enrollment. Targeted No inhaled concentration will be maintained between 140 and 180 ppm. The gas will be delivered through a CPAP circuit ensuring an end-expiratory pressure between 2 and 10 cmH2O or through a non-rebreathing mask without positive end-expiratory pressure, depending on the clinical needs of the subject.
Sponsors
Massachusetts General Hospital
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study includes a randomized, parallel arm clinical trial in which subjects will be randomized to receive either inhaled nitric oxide (in addition to the standard of care) or the standard of care alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Laboratory confirmed COVID19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 IgM/IgG antibodies. 2. Hospital admission with at least one of the following: 1. fever ≥ 36.6 °C from axillary site; or ≥ 37.2°C from oral site; or ≥ 37.6°C from tympanic or rectal site. 2. Respiratory rate ≥ 24 bpm 3. cough 3. Spontaneous breathing with or without hypoxia of any degree. Gas exchange and ventilation maybe assisted by any continuous continuous airway pressure (CPAP), or any system of Non Invasive Ventilation (NIV), with Positive End-Expiratory Pressure (PEEP) ≤ 10 cmH2O.
Exclusion criteria
1. Tracheostomy 2. Therapy with high flow nasal cannula 3. Any clinical contraindications, as judged by the attending physician 4. Patients enrolled in another interventional study 5. Hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours 6. Previous intubation for COVID-19 7. Patient not committed to full support (DNR, DNI or CMO) 8. Patient requiring oxygen at home for lung comorbidities 9. Primary cause of hopitalization not due to COVID-19
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Mild/Moderate COVID-19 Requiring Intubation and Mechanical Ventilation | 28 days | The primary outcome will be the number of participants requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 28 days | Proportion of deaths from all causes |
| Time to Clinical Recovery | 28 days | Time from initiation of the study to discharge or to normalization of fever (defined as \<36.6°C from axillary site, or \< 37.2°C from oral site or \< 37.8°C from rectal or tympanic site), respiratory rate (\< 24 bpm while breathing room air), alleviation of cough (defined as mild or absent in a patient reported scale of severe \>\>moderate\>\>mild\>\>absent) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for 72 hours. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORLorenzo Berra, MD
Massachusetts General Hospital
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 50 years |
| Comorbidities Cerebrovascular Disease | 1 participants |
| Comorbidities Chronic Kidney Disease | 3 participants |
| Comorbidities Chronic Pulmonary Disease | 3 participants |
| Comorbidities Coronary Heart Disease | 1 participants |
| Comorbidities Diabetes | 14 participants |
| Comorbidities Hypertension | 14 participants |
| Comorbidities Immune Deficiency | 1 participants |
| Comorbidities Malignancy | 0 participants |
| Comorbidities None | 9 participants |
| Comorbidities Other | 5 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 1 / 33 |
| other Total, other adverse events | 0 / 29 | 0 / 33 |
| serious Total, serious adverse events | 0 / 29 | 0 / 33 |
Outcome results
None listed